Name: LC-2
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

White Solid

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

Shipping

Room temperature in continental US; may vary elsewhere.

IUPACName

(2S,4R)-1-[(2S)-2-[3-[3-[(2S)-2-[[7-(8-chloronaphthalen-1-yl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidin-1-yl]propoxy]propanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

(2S,4R)-1-((S)-2-(3-(3-((S)-2-(((7-(8-chloronaphthalen-1-yl)-4-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-1-yl)propoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Density

1.297±0.06 g/cm3

InChI Key

ZCGQZLKPUVGCBQ-HLMPTVQRSA-N

InChI

InChI=1S/C59H71ClFN11O7S/c1-37(61)56(76)71-27-26-70(32-42(71)19-22-62)54-45-20-25-69(48-14-7-11-40-10-6-13-46(60)51(40)48)34-47(45)65-58(67-54)79-35-43-12-8-23-68(43)24-9-28-78-29-21-50(74)66-53(59(3,4)5)57(77)72-33-44(73)30-49(72)55(75)63-31-39-15-17-41(18-16-39)52-38(2)64-36-80-52/h6-7,10-11,13-18,36,42-44,49,53,73H,1,8-9,12,19-21,23-35H2,2-5H3,(H,63,75)(H,66,74)/t42-,43-,44+,49-,53+/m0/s1

SMILES

N#CCC1N(C(=O)C(F)=C)CCN(C2=NC(=NC3=C2CCN(C4=CC=CC=5C=CC=C(Cl)C54)C3)OCC6N(CCCOCCC(=O)NC(C(=O)N7CC(O)CC7C(=O)NCC=8C=CC(=CC8)C=9SC=NC9C)C(C)(C)C)CCC6)C1

Pub Chem ID

154727765

Mechanism

Target: Targets KRAS G12C mutant protein for experimental targeted protein degradation studies.

Binding Site: Binds the KRAS G12C switch-II pocket and VHL substrate-recognition domain to support productive ternary complex formation.

Mechanism of Action: LC-2 is designed for use in PROTAC or targeted protein degradation experiments directed toward KRAS G12C mutant protein. The bifunctional molecule links a target-recognition element to VHL, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated Kinase Degradation: LC-2 is employed in the targeted degradation of specific kinases, facilitating the study of kinase-driven signaling pathways. This application allows researchers to dissect the role of kinases in cellular processes by selectively degrading them, offering insights into potential therapeutic targets for diseases linked to aberrant kinase activity.

• Targeted Oncoprotein Degradation: Utilizing LC-2, researchers can achieve the selective degradation of oncoproteins, which are often implicated in cancer progression. This approach enables the exploration of oncoprotein functions and interactions, aiding in the identification of novel cancer treatment strategies by removing these critical drivers of tumorigenesis.

• PROTAC-Enhanced Proteostasis Studies: LC-2 aids in the investigation of cellular protein homeostasis by selectively degrading proteins involved in proteostasis regulation. This application provides a powerful tool for understanding how cells maintain protein balance and the consequences of proteostasis disruption, which is crucial in neurodegenerative diseases research.

• Degradation of Transcription Factors: LC-2 enables the targeted degradation of transcription factors, offering a unique method to study gene expression regulation. By removing specific transcription factors, researchers can analyze their direct effects on gene networks, enhancing the understanding of transcriptional control mechanisms and their implications in various biological contexts.

1. Targeted degradation of oncogenic KRASG12C by VHL-recruiting PROTACs.

Bond, M.J., Chu, L., Nalawansha, D.A., Li, K. and Crews, C.M., 2020. ACS central science, 6(8), pp.1367-1375.

KRAS is mutated in ~20% of human cancers and is one of the most sought-after targets for pharmacological modulation, despite having historically been considered "undruggable." The discovery of potent covalent inhibitors of the KRASG12C mutant in recent years has sparked a new wave of interest in small molecules targeting KRAS. While these inhibitors have shown promise in the clinic, we wanted to explore PROTAC-mediated degradation as a complementary strategy to modulate mutant KRAS. Herein, we report the development of LC-2, the first PROTAC capable of degrading endogenous KRASG12C. LC-2 covalently binds KRASG12C with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRASG12C degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRASG12C cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
1 mM	0.88 mL	4.41 mL	8.83 mL
5 mM	0.18 mL	0.88 mL	1.77 mL
10 mM	0.09 mL	0.44 mL	0.88 mL
50 mM	0.02 mL	0.09 mL	0.18 mL

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂